Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Substance P Antagonists as a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury Robert Vink and Corinna van den Heuvel School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia, 5005 Summary: Although a number of secondary injury factors are been implicated in learning and memory, mood and anxiety, known to contribute to the development of morphological in- stress mechanisms, emotion-processing, migraine, emesis, jury and functional deficits following traumatic brain injury, pain, and seizures, all of which may be adversely affected accumulating evidence has suggested that neuropeptides, after brain injury. Inhibition of post-traumatic substance P and in particular substance P, may play a critical role. Sub- activity, either by preventing release or by antagonism of the stance P is released early following acute injury to the CNS neurokinin-1 receptor, has consistently resulted in a pro- as part of a neurogenic inflammatory response. In so doing, found decrease in development of edema and marked im- it facilitates an increase in the permeability of the blood– provements in functional outcome. This review summarizes brain barrier and the development of vasogenic edema. At the current evidence supporting a role for substance P in the cellular level, substance P has been shown to directly acute brain injury. Key Words: Neurotrauma, inflammation, result in neuronal cell death; functionally, substance P has edema, substance P, tachykinins. INTRODUCTION to prevent further injury and improve outcome. Accord- ingly, a significant research effort has been directed at Traumatic brain injury (TBI) is the leading cause of identifying secondary injury factors and then developing death and disability in people under 40 years of age in novel therapies that may attenuate, or even prevent, their developed countries.1 Although the costs for treatment, action. rehabilitation, and care of such individuals is measured in billion of dollars annually, no effective treatment cur- Secondary injury factors identified to date include re- rently exists. Brain injury results in the development of lease of neurotransmitters (such as excitatory amino ac- neurologic deficits through two main mechanisms, com- ids), ion changes, calpain activation, oxidative stress, blood–brain barrier (BBB) disruption, edema, and bioen- prising primary and secondary events. Primary events are 2 made up of the mechanical processes that occur at the ergetic failure. Of these, profound edema has been time of the trauma, including tissue shearing, laceration, clearly associated with mortality following severe TBI, and stretching of nerve fibers.2 Preventive measures such as well as in the development of significant morbidity in 4 as helmets, airbags, and seatbelts are the only interven- up to 50% of surviving TBI patients. It is widely ac- tions that can prevent or attenuate these primary events. cepted that the development of edema has adverse con- In contrast, secondary injury evolves over minutes to sequences on outcome through effects on intracranial 5 days and even months after the initial event and is made pressure (ICP). Current protocols for the management up of delayed biochemical and physiological factors that of elevated ICP include induction of hyperventilation or are initiated by the primary event. These secondary in- hypothermia, pharmacological regimens such as admin- jury factors are thought to account for much of the mor- istration of diuretics or hyperosmotic agents, or surgical bidity following brain injury,3 and their delayed nature procedures such as drainage of CSF and decompressive 6 presents opportunities for interventional pharmacology craniectomy. Unfortunately, these interventions have essentially been inadequate, largely because they target the end-product of edema formation and not the funda- mental issue of what specific mechanisms are associated Address correspondence and reprint requests to: Robert Vink, Ph.D., School of Medical Sciences, The University of Adelaide, SA 5005, with its development. Recent studies have suggested that Australia. E-mail: [email protected]. neuropeptides, and in particular substance P (SP), may 74 Vol. 7, 74–80, January 2010 © The American Society for Experimental NeuroTherapeutics, Inc. SUBSTANCE P ANTAGONISTS 75 play a critical role in edema formation through actions at the level of the BBB.7,8 This alternative mechanistic approach to the management of post-traumatic edema and elevated ICP potentially offers a number of exciting opportunities. KININS AND SUBSTANCE P Substance P is a member of the tachykinin family of kinins. Kinins are a group of peptide mediators that have proinflammatory actions, some of which are mediated via the vasculature where they cause vasodilation and increased vascular permeability. The tachykinins, includ- ing SP, calcitonin gene-related peptide (CGRP), and neu- rokinin A, share specific amino acid sequences that allow them to be sorted into the tachykinin family. This family of compounds represents one of the largest peptide fam- ilies described in animals.9 Substance P was first identi- fied as a crude extract with potent hypotensive and smooth muscle contractile properties isolated from 10 FIG. 1. Schematic of neurogenic inflammation demonstrating equine brain. It was identified in high concentrations in how the release of neuropeptides, and particularly of substance the dorsal root of the spinal cord, leading to the proposal P, is associated with the development of vascular permeability and edema formation. CGRP ϭ calcitonin gene-related peptide; that it is a neuronal sensory transmitter associated with NK ϭ neurokinin receptor; TRPVR ϭ transient receptor potential pain transmission.11 Today, it is accepted that SP is vanilloid receptor. released from both central and peripheral endings of sensory neurons and functions as a neurotransmitter.12 NEUROGENIC INFLAMMATION Its release, along with that of the other tachykinins, pro- Originally described as vasodilation of lower limb duces effects via tachykinin receptors, thereby playing a vessels following stimulation of the dorsal root gan- significant role in the neural component of inflammation glia,20 the concept of neurogenic inflammation (FIG. 1) known as neurogenic inflammation (discussed in the next has evolved to encompass vasodilation, plasma extrava- section). sation, and neuronal hypersensitivity caused by the re- The other distinct family of kinins, the bradykinins, is lease of neuropeptides from sensory neurons.21 Several formed from the cleavage of the plasma globulin kinino- neuropeptides have been implicated in this process, with gen, by plasma and tissue proteases known as kallikreins. CGRP identified as being associated with the vasodila- The active peptides formed by this proteolytic cleavage tion of arterioles and SP being thought to enhance are bradykinin and kallidin (lysyl bradykinin), and these plasma protein extravasation as well as leukocyte adhe- kinins produce their effects through two subtypes of sion to endothelial cells in postcapillary venules.22 Ce- bradykinin receptors, B1 and B2. Bradykinin receptor rebral blood vessels are surrounded by a dense supply of antagonists have been shown to improve neurological sensory neurons, as are virtually all blood vessels of the 13 outcome following TBI, even when administered up body, and these fibers contain both CGRP and SP. Any to 4 h post trauma. This neuroprotection is thought to release of the neuropeptides around the cerebral vascu- be mediated, in part, by attenuating production of lature would initiate neurogenic inflammation, a concept inducible nitric oxide synthase (iNOS) and prostaglan- supported by the fact that neuropeptides are a therapeutic din E2,14 as well as edema formation13 and increases target to reduce vascular permeability in migraine.23 Fol- in ICP.15,16 An anti-inflammatory component has also lowing TBI, both enhanced vascular permeability of the been suggested,17 as well as inhibitory effects on re- BBB and cerebral vasodilation would potentially con- active oxygen species generation.18 There is also ev- tribute to an increase in ICP. idence, however, to suggest that bradykinin itself may Peptide-containing primary sensory neurons are charac- have glial cell-mediated neuroprotective and anti-in- terized by their unique sensitivity to capsaicin, the pungent flammatory effects in the CNS, induced via attenua- ingredient found in capsicum peppers.24 The transient re- tion of cytokine release from activated microglia, as ceptor potential vanilloid receptor-1 (TRPVR1) is the site well as by upregulation of neurotrophic factor produc- of binding by capsaicin,25 and this receptor has been tion in astrocytes.19 identified as a nonselective cation channel whose endog- Neurotherapeutics, Vol. 7, No. 1, 2010 76 VINK AND VAN DEN HEUVEL enous stimulants include heat (Ͼ43°C) and protons (FIG. vestigated the role of classical inflammation in edema 1). Some primary sensory neurons are selectively stim- formation following TBI,32,33 to date few studies have ulated by capsaicin; at higher concentrations, capsaicin examined the role of neurogenic inflammation. Nimmo kills these neurons, blocking the genesis of subsequent et al.7 were among the first to do so, by demonstrating neurogenic inflammatory responses.24 These neurons are that chronic administration of capsaicin prior to TBI defined as capsaicin-sensitive, because of the specific